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|Ref Type||Journal Article|
|Authors||Napolitano R, De Matteis S, Carloni S, Bruno S, Abbati G, Capelli L, Ghetti M, Bochicchio MT, Liverani C, Mercatali L, Calistri D, Cuneo A, Menon K, Musuraca G, Martinelli G, Simonetti G|
|Title||Kevetrin induces apoptosis in TP53 wild‑type and mutant acute myeloid leukemia cells.|
|Date||2020 Aug 11|
|Abstract Text||Tumor protein p53 is a key regulator of several cellular pathways, including DNA repair, cell cycle and angiogenesis. Kevetrin exhibits p53‑dependent as well as‑independent activity in solid tumors, while its effects on leukemic cells remain unknown. The aim of the present study was to analyze the response of acute myeloid leukemia (AML) cell lines (TP53 wild‑type: OCI‑AML3 and MOLM‑13; and TP53‑mutant: KASUMI‑1 and NOMO‑1) to kevetrin at a concentration range of 85‑340 µM. The cellular and molecular effects of the treatment were analyzed in terms of cell growth, viability [Annexin V‑propidium iodide (PI) staining] and cell cycle alterations (PI staining). Gene expression profiling, western blotting and immunofluorescence were performed to elucidate the pathways underlying kevetrin activity. Pulsed exposure exerted no effect on the wild‑type cells, but was effective on mutant cells. After continuous treatment, significant cell growth arrest and apoptosis were observed in all cell lines, with TP53‑mutant models displaying a higher sensitivity and p53 induction. Kevetrin also displayed efficacy against TP53 wild‑type and mutant primary AML, with a preferential cytotoxic activity against blast cells. Gene expression profiling revealed a common core transcriptional program altered by drug exposure and the downregulation of glycolysis, DNA repair and unfolded protein response signatures. These findings suggest that kevetrin may be a promising therapeutic option for patients with both wild‑type and TP53‑mutant AML.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|TP53||I255N||missense||unknown||TP53 I255N lies within the DNA-binding domain of the Tp53 protein (PMID: 15510160). I255N has been identified in the scientific literature (PMID: 32945487), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Apr 2022).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|TP53 I255N||acute myeloid leukemia||predicted - sensitive||thioureidobutyronitrile||Preclinical - Patient cell culture||Actionable||In a preclinical study, Kevetrin (thioureidobutyronitrile) treatment resulted in apoptosis of leukemic blast cells and decreased cell viability in patient-derived acute myeloid leukemia cells harboring TP53 I255N in culture (PMID: 32945487).||32945487|
|TP53 R248Q||acute myeloid leukemia||predicted - sensitive||thioureidobutyronitrile||Preclinical - Cell culture||Actionable||In a preclinical study, Kevetrin (thioureidobutyronitrile) treatment resulted in apoptosis, decreased cell viability, elevated expression of Tp53 target genes, and increased Tp53 nuclear localization in an acute myeloid leukemia cell line harboring TP53 R248Q in culture (PMID: 32945487).||32945487|
|TP53 C242fs||acute myeloid leukemia||predicted - sensitive||thioureidobutyronitrile||Preclinical - Cell culture||Actionable||In a preclinical study, Kevetrin (thioureidobutyronitrile) treatment resulted in apoptosis, decreased cell viability, altered cell cycle progression, elevated expression of Tp53 target genes, and increased Tp53 nuclear localization in an acute myeloid leukemia cell line harboring TP53 C242fs in culture (PMID: 32945487).||32945487|